Gambogenic acid derivatives, preparation method and application thereof

ABSTRACT

Gambogenic acid derivatives having a structure shown as Formula (I) or (II), salts, preparation method and application thereof in the treatment of tumor. Compared with gambogenic acid, the gambogenic acid derivatives exhibit more potent anti-tumor activities.

FIELD OF THE INVENTION

The present invention relates to an antitumor drug, and its preparationmethod and application, in particular to gambogenic acid derivatives,their preparation and use.

BACKGROUND OF THE INVENTION

As people have longer lifespan with changes in diet habits, cancerpatients have increased from year to year. WHO data shows that cancerhas become a major fatal disease, and cancer patients will continue toincrease; cancer as the leading cause of death in 2008 accounted for13.8%, and is expected to account for more than 15% in 2015.

Currently, the clinical treatments of malignant tumors are primarily bysurgery, radiotherapy, and chemotherapy, either alone or in combination.In recent years, the survival time of cancer patients was significantlyprolonged by chemotherapy. However, existing anticancer drugs stillcannot meet the clinical needs due to the high variability of tumorcells and the generation of multi-drug resistance. Cytotoxic drugs as amajor component of chemotherapy in cancer treatment have played a veryimportant role. So far, these drugs still occupy major market share ofanticancer drugs, including drugs obtained from natural products, suchas Taxol drugs, etc., and they become common anti-cancer drugs inclinical practices because of their therapeutic effects.

Nevertheless, cytotoxic chemotherapy drugs can cause multi-drugresistance of the tumor cells after long-term using, which reduce theefficacy of these drugs, such that doctors increase drug dosage toimprove efficacy, thereby reducing drug security. Adverse reactionswould be caused because cytotoxic drugs kill tumor cells while alsokilling normal cells. All cytotoxic drugs usually lead to adversereactions in patients, and the adverse reactions are increasing inaccordance with the increasing dosage. Therefore, the maximum dose ofchemotherapeutic drug is strictly limited. In other words, it is notfeasible to increase administration to improve drug efficacy when thedrug resistance occur. The only feasible way is to replace anothereffective chemotherapy drug. Thus, more effective chemotherapy drugsshall be developed for clinicians, and the research and development ofnew and effective anticancer drugs is undoubtedly one of the most urgenttasks.

Garcinia (Gamboge) is yellow resin from gamboge trees that grow inIndia, Vietnam, and in Yunnan, Hunan, and Hubei areas in China, and canbe used as a yellow pigment in painting. The book “Compendium of MateriaMedica” authored by Li Shizhen of the Ming Dynasty cited that “Garciniaused for painter was decocted”. Garcinia is one of the Chinese medicinesthat inhibit tumor growth and refractory carbuncle.

Gambogenic acid (as shown in Formula X, numbers representing a carbonsequence) is the active ingredient of Garcinia. It has been reportedthat gambogenic acid can inhibit tumor growth in vitro and in vivo,induce tumor cells apoptosis, and show stronger anti-tumor activitiesfor a variety of malignant tumors due to it's characteristic ofselectively inhibiting tumor growth.

Bao-Xi, Qu etc. (Chinese Journal of Clinical Oncology, 1991, Volume 18,No. 1, page 50) demonstrated that gambogenic acid has broad anti-canceractivities, less toxicity, and better inhibitory effect for inhibitingS180, ARS ascites carcinoma, P388 leukemia, Lewis lung cancer and La795lung cancer. In comparison with garcinia acid (another anti-tumorcomponents extracted from Garcinia), gambogenic acid is stronger forinhibiting mouse leukemia L1210, and the highest survival rate ofgambogenic acid is extended up to 2.45 times than that of garcinia acid.The research results of cell cycle of L1210 leukemia show thatgambogenic acid (intravenous infusion, 10 mg/kg) can inhibit G1-S phasetransition by reducing S phase cells and promoting G1 phase cells.

Cheng Hui, etc. (Herbal, 2008, Volume 39 No. 2, page 236) observedproliferative inhibition of a variety of malignant cells by gambogenicacid via MTT method. The result showed that gambogenic acid can besignificantly used for proliferative inhibition of human colon cancercells (HCT-8), human hepatoma cells (BEL-7402), human gastric cancercells (BGC-823), human non-small cell lung cancer cells (A549), andhuman ovarian cancer (A2780).

Gambogenic acid is a common active ingredient in traditional Chinesemedicine. The extraction process of gambogenic acid is simple, low cost,and gambogenic acid can be obtained plentifully for developinganti-tumor drug.

Patent CN1718183A disclosed gambogenic acid preparation can inhibithuman hepatoma BEL-7402, human hepatoma 7721, human breast cancer MCF-7,and human cervical carcinoma Hela cells, wherein the human hepatomacells are most sensitive. Patent CN1718184A disclosed gambogenic acidcomplexes combined with anticancer drugs such as moroxydine, amantadine,cytarabine, and matrine for the treatment of liver cancer, colon cancer,and lung cancer due to prominent efficacy and lower irritation andtoxicity. Patent CN101947204A disclosed solid lipid nanoparticles ofgambogenic acid: preparing gambogenic acid to make solid nanoparticlesto improve bioavailability, reduce irritation, and prolong efficacytime.

In comparison with the current clinical drugs, gambogenic acid obtainedfrom nature has shortcomings including that the activity is not strongenough, and safe dose is small, thereby limiting its development andapplication. Thus, the structure of the gambogenic acid has to bemodified to improve its activity and druggability.

SUMMARY OF THE INVENTION

To overcome the shortcomings that the activity of the gambogenic acid isnot strong enough, the objective of the present invention is to providea gambogenic acid derivative that has better anti-tumor activity, so asto provide leading compounds for antitumor researches or new candidatecompounds for antitumor drugs.

In one aspect, the present invention is to provide a gambogenic acidderivative, the gambogenic acid derivative represented by of themolecular structure represented in any one of Formula (I) to (II):

wherein A is —CO— or —HC(OH)—; R¹ is selected from:

1) —OR⁴;

wherein R⁴ is selected from the group consisting of any one of thefollowing: hydrogen, straight chain or branched chain C₁ to C₁₀ alkylgroup, or alkyl group containing optionally 1 to 3 substituted groupsincluding oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group,C₁ to C₁₀ alkoxycarbonyl group, aryloxy group; C₃-C₈ cycloalkyl group,C₁ to C₁₀ alkyl group substituted by 1, 2 or 3 heteroatoms; alkylarylgroup including C₁ to C₁₀ alkyl group substituted by aromatic group andC₁ to C₁₀ alkyl group optionally substituted by 1 to 3 substitutedaromatic groups including acyl group, —OCH₂O—, halogen, haloalkyl group,aryl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxylgroup, acyloxy group, C₁ to C₁₀ alkoxy group; heteroarylalkyl groupincluding C₁ to C₁₀ alkoxy group substituted by heteroaryl group, and C₁to C₁₀ alkyl group optionally substituted by any heteroaryl groupincluding heteroaryl group, C₁ to C₁₀ alkyl group, aralkyl group, C₃ toC₈ cycloalkyl group, C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group,aromatic group and C₁ to C₆ amide group; straight chain or branchedchain C₂ to C₁₀ alkenyl group or alkynyl group including optionally 1 to3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group and C₁ to C₁₀heteroalkyl group including 1, 2 or 3 heteroatoms; C₄ to C₁₀cycloalkenyl, C₄ to C₁₀ alkynyl group, or alkynyl group includingoptionally 1 to 3 substituted groups including oxygen group, halogen,aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxygroup, amide group, C₁ to C₆ acyl group, C₁ to C₁₀ alkoxy group, aryloxygroup and C₁ to C₁₀ heteroalkyl group including optionally 1, 2 or 3heteroatoms.

2) —NR⁵R⁶;

wherein R⁵ and R⁶ may be identical or different, and are independentlyselected from any one of the substituted groups as follows: hydrogen;straight chain or branched C₁ to C₁₀ alkyl group or C₁ to C₁₀ alkylgroup containing optionally 1 to 3 substituted groups including oxygengroup, halogen, C₁ to C₁₀ alkoxy group, acyloxy group, C₁ to C₁₀alkoxyacyl group, aryloxy group; C₃ to C₈ cycloalkyl group; C₁ to C₁₀alkyl group substituted by 1, 2 or 3 heteroatoms; alkylaryl groupincluding C₁ to C₁₀ alkyl group substituted by aromatic group and C₁ toC₁₀ alkyl group substituted by optionally 1 to 3 substituted aromaticgroups including acyl group, —OCH₂O—, halogen, haloalkyl group, hydroxylgroup, aryl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkyl group,acyloxy group, C₁ to C₁₀ alkoxy group; heteroarylalkyl group includingC₁ to C₁₀ alkoxy group substituted by heteroaryl group, and C₁ to C₁₀alkyl group optionally substituted by any heteroaryl group includingheteroaryl group, C₁ to C₁₀ alkyl group, aralkyl group, C₃ to C₈cycloalkyl group, C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group,aromatic group and C₁ to C₆ amide group; straight chain or branchedchain C₂ to C₁₀ alkenyl group or alkenyl group containing optionally 1to 3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy groupand C₁ to C₁₀ heteroalkyl group containing 1, 2 or 3 heteroatoms; C₄ toC₁₀ cycloalkenyl, C₄ to C₁₀ alkynyl group, or alkynyl group containingoptionally 1 to 3 substituted groups including oxygen group, halogen,aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxygroup, amide group, C₁ to C₆ acyl group, C₁ to C₁₀ alkoxy group, aryloxygroup and C₁ to C₁₀ heteroalkyl group including 1, 2 or 3 heteroatoms.

wherein s and t are positive integers, and the sum of s and t is anatural number of 2 to 10;

m is 0, 1, 2 or 3, and represents the number of the substituted group onR⁷ of the ring;

n is 0, 1, 2 or 3, and represents the number of B on the ring; B iscarbon, nitrogen or oxygen;

the groups of R⁷, R⁸ are identical with the group of R⁵, or carbonylgroup, imino group, oxime group, aliphatic group; or when B is tertiarynitrogen, R⁸ is oxygen, and so as to form nitrogen oxides with B;

R² is selected from any one of the substituted groups as follows:hydrogen, straight chain or branched chain C₁ to C₁₀ alkyl group, C₃ toC₈ cycloalkyl group, aromatic group or aromatic group substituted by C₁to C₁₀ alkyl, heteroaryl group, and acyl group substituted by C₁ to C₁₀alkyl or acyl group substituted by aromatic group;

R³ is selected from any one of the substituted groups as follows:hydrogen, alkyl group substituted by C₁ to C₁₀ acyl group or aryl groupsubstituted by aromatic group;

R is selected from any one of the substituted groups as follows:hydrogen, straight chain or branched chain C₁ to C₁₀ alkyl group, C₃ toC₈ cycloalkyl group, straight chain or branched chain C₂ to C₁₀ alkenylgroup or C₃ to C₈ cycloalkenyl group, phenyl group or phenyl groupsubstituted by C₁ to C₁₀ alkyl group, C₂ to C₆ alkynyl group,nucleophiles containing secondary amine group including straight chainor branched chain alkyl amino group, straight chain or branched chainalkenyl amino group; aromatic or aromatic alkylamino group, the amineobtained by addition of chain alkynyl amine group and α,β-unsaturatedketones.

However, R, R², R³, R⁴ are not simultaneously hydrogen on Formula (I).

In a preferred embodiment, according to the present invention, theabove-described gambogenic acid derivative is represented by themolecular structure as shown in any one of Formula (III) to (V):

In a preferred embodiment, according to the present invention, theabove-described gambogenic acid derivative is represented by themolecular structure as shown in Formula (VI):

In the formula of the gambogenic acid derivative as above-described ofthe present invention, R¹ is preferably selected from any one of thefollowing:

1) —OR⁴,

wherein R⁴ is selected from the group consisting of any one of thefollowing: hydrogen, methyl group, ethyl group, propyl group, isopropylgroup, butyl group, isobutyl group, tert-butyl group, hexyl group, octylgroup, C₁ to C₁₀ alkyl group substituted by any 1 to 3 substitutedgroups including oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxygroup, C₁ to C₁₀ alkoxyacyl group, aromatic group; cyclohexyl group,cyclopentyl group; cyclopropyl group, —CH₂CH₂OCH₂CH₃,—CH₂CH₂OCH₂CH₂OCH₂CH₃, —CH₂CH₂NHCH₃, —OCH₂O—, halogen, haloalkyl group,hydroxyl group, —CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂OCH₂CH₂NCH₃, benzyl group,phenethyl group, phenylpropyl group, tetrahydro-pyrrolyl group,piperidinyl group, morpholinyl group, —CH₂CH₂OCH₂CH₂OCH₂NHCH₃,—CH₂CH₂NHCH₂CH₃, —CH₂(N-ethyl-pyrrolidine), —CH₂C(CH₃)CH₂N(CH₃), C₁ toC₁₀ alkyl group substituted by optionally 1 to 3 substituted aromaticgroups including acyl group, aryl group, C₃ to C₈ cycloalkyl group, C₁to C₁₀ alkyl group, hydroxyl group, acyloxy group, C₁ to C₁₀ alkoxygroup; heteroarylalkyl group including C₁ to C₁₀ alkoxy groupsubstituted by heteroaryl group, and C₁ to C₁₀ alkyl group optionallysubstituted by any heteroaryl group including heteroaryl group, C₁ toC₁₀ alkyl group, aralkyl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀alkoxycarbonyl group, carbamoyl group, aromatic group and C₁ to C₆ amidegroup; straight chain or branched C₂ to C₁₀ alkenyl group or alkenylgroup containing optionally 1 to 3 substituted groups including oxygengroup, halogen, aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxygroup, acyloxy group, amide group, C₁ to C₆ amine acyl group, C₁ to C₁₀alkoxy group, aryloxy group, and C₁ to C₁₀ heteroalkyl group containing1, 2 or 3 heteroatoms; C₄ to C₁₀ cycloalkenyl, C₄ to C₁₀ alkynyl group,or C₄ to C₁₀ alkynyl group containing optionally 1 to 3 substitutedgroups including oxygen group, halogen, aromatic ring group, aralkylgroup, C₁ to C₁₀ alkoxy group, acyloxy group, amide group, C₁ to C₆amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy group and C₁ to C₁₀heteroalkyl group containing 1, 2 or 3 heteroatoms.

2) —NR⁵R⁶;

wherein R⁵ and R⁶ may be identical or different, and are independentlyselected from any one of the substituted groups as follows: hydrogen,methyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl butyl group, tert-butyl group, hexyl group, octyl group; C₁ toC₁₀ alkyl group containing optionally 1 to 3 substituted groupsincluding hydroxyl group, amino group, C₁ to C₁₀ alkylamino group,oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group, C₁ to C₁₀alkoxyacyl group, aryloxy group; cyclohexyl group, cyclopentyl group,cyclopropyl group, —CH₂CH₂OCH₂CH₃, —CH₂CH₂OCH₂CH₂OCH₂CH₃, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂OCH₂CH₂NCH₃, —CH₂(N-ethyl-pyrrolidine),tetrahydro-pyrrolyl group, piperidinyl group, morpholinyl group, benzylgroup, —CH₂CH₂OCH₂CH₂OCH₂NHCH₃, —CH₂CH₂NHCH₂CH₃, phenethyl group,phenylpropyl group, —CH₂C(CH₃)CH₂N(CH₃); C₁ to C₁₀ alkyl groupoptionally substituted by 1 to 3 substituted aromatic groups includingacyl group, —OCH₂O—, halogen, haloalkyl group, aryl group, C₃ to C₈cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxyl group, acyloxy group,C₁ to C₁₀ alkoxy group; heteroarylalkyl group including C₁ to C₁₀ alkoxygroup substituted by heteroaryl group, and C₁ to C₁₀ alkyl groupoptionally substituted by any heteroaryl group including heteroarylgroup, C₁ to C₁₀ alkyl group, aralkyl group, C₃ to C₈ cycloalkyl group,C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group, aromatic group and C₁to C₆ amide acyl group; straight chain or branched chain C₁ to C₁₀alkenyl group or alkynyl group containing optionally 1 to 3 substitutedgroups including oxygen group, halogen, aromatic ring group, aralkylgroup, C₁ to C₁₀ alkoxy group, acyloxy group, amide group, C₁ to C₆amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy group and C₁ to C₁₀heteroalkyl group containing 1, 2 or 3 heteroatoms; C₄ to C₁₀cycloalkenyl, C₄ to C₁₀ alkynyl group, or C₄ to C₁₀ alkynyl groupcontaining optionally 1 to 3 substituted groups including oxygen group,halogen, aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group,acyloxy group, amide group, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxygroup, acyloxy group, and C₁ to C₁₀ heteroalkyl group containing 1, 2 or3 heteroatoms.

R³ is selected from any one of the substituted groups as follows:hydrogen, formyl group, acetyl group, carbamoyl group, phenyl group, andphenylacetyl group.

R² is selected from any one of the substituted groups as follows:hydrogen, methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, tert-butyl group, hexyl group, octyl group,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, cycloheptyl group, benzyl group, phenethyl group, furyl group,pyranyl group, 2H-pyrrolyl group, pyrrolyl group, imidazolyl group,pyrazolyl group, pyridyl group, formyl group, acetyl group, carbamoylacyl group, phenyl group, and phenylacetyl group.

R is selected from any one of the substituted groups as follows: methylgroup, ethyl group, propyl group, isopropyl group, butyl group, isobutylgroup, tert-butyl group, hexyl group, octyl group, cyclohexyl group,cyclopentyl group, vinyl group, butene group, hexenyl group,cyclohexenyl group, cyclopentenyl group, phenyl group, benzyl group,phenethyl group, phenylpropyl group, butynyl group, hexynyl group,morpholinyl group, piperidinyl group, and piperazinyl group.

In a preferred embodiment, according to the present invention, in theformula of the above-described gambogenic acid derivative:

A is —CO— or —HC(OH)—

R¹ is selected from:

wherein R⁷ is selected from the group consisting of any one of thefollowing: substituted group as defined in R⁵, carbonyl group, alkylenegroup, oxime group;

m, n is 0, 1, 2 or 3;

B is carbon, nitrogen or oxygen;

the group of R⁸ is identical as the group defined in R⁵, or R⁸ is oxygenso as to form nitrogen oxides with B.

wherein R⁷ is selected from the group consisting of any one of thefollowing:

the substituted group as in defined R⁵, carbonyl group, imino group,aliphatic group;

m, n is 0, 1, 2 or 3;

B is carbon, nitrogen or oxygen;

the group of R⁸ is identical with the group as defined in R⁵, or R⁸ isoxygen so as to form nitrogen oxides with B.

In a second aspect, the present invention is to provide a salt of thegambogenic acid derivatives, the salt can be 1) the salt formed withinorganic acid such as hydrochloric acid salts, carbonates, sulfates; 2)the salt formed with an organic base; or 3) the salt formed with aninorganic base; 4) the salt formed with organic acid.

In a third aspect, the present invention is to provide a method forpreparing gambogenic acid derivative, gambogenic acid derivative asshown in Formula (VII) is obtained by R² and R³ introduced to thegambogenic acid or gambogenic acid derivative of Formula (VI), whereinthe order of R² and R³ introduction may be adjusted;

wherein R³ is condensed with R³X acid halide or acid anhydride (R³)₂O; Xis Cl, Br or I;

When R² is acyl group substituted by alkyl group, acyl group substitutedby aromatic group, introduced in the same method with the introductionof R³; when R² is alkyl group, cycloalkyl group or heteroaryl group, theintroduction is via etherification reaction by halo of R².

Then, the carbonyl group of C₆ carbon was prepared by reduction toobtain gambogenic acid derivatives as shown in Formula (VIII), and/or byesterification or acidification with R⁴OH, R⁵R⁶NH or

to obtain gambogenic acid derivatives as shown in Formula (III).

The reaction solvent of condensation of R² and/or R³ can be methylchloride (such as dichloromethane, chloroform), chlorinated ethane,tetrahydrofuran, etc. The reaction temperature is preferably between 20°C. to 40° C. The deacid reagent (such as triethylamine, pyridine) orcatalyst (such as DMAP) can be added accordingly. When R² and R³ aredifferent, the molar ratio of acid halide or acid anhydride andgambogenic acid is 5:1.

Halide of R² can be R²Br, R²I. Preferably, the reaction conditioncontains the sodium carbonate, potassium carbonate, cesium carbonate orbicarbonate. Preferably, the reaction solvent is a polar solvent such asDMA or DMF.

The reducing agents used for reduction reaction on C₆ include such assodium borohydride, lithium borohydride, useful solvents including C₁ toC₆ alcohol and tetrahydrofuran.

In a fourth aspect, the present invention is to provide a second methodfor preparing gambogenic acid derivative, wherein gambogenic acid,gambogenic acid derivatives as shown in Formula (VII), or gambogenicacid derivatives as shown in Formula (VIII) are used as raw material;the double bond is oxidized between C₉ and C₁₀ to obtain gambogenic acidderivatives as shown in Formula (II) by peroxidant in alkalineconditions.

Preferably, the concentration of hydrogen peroxide is 30%. The reactionsolvent is preferably water, the base is a water-soluble hydroxide suchas NaOH, KOH, etc.

In a fifth aspect, the present invention is to provide a thirdpreparation method of gambogenic acid derivative, wherein gambogenicacid derivative as shown in Formula (I) was prepared by 1,4-addition ondouble bond between C₉ and C₁₀ by the organic copper reagent RCu withgambogenic acid, gambogenic acid derivative as shown in Formula (VII),or gambogenic acid derivative as shown in Formula (VIIII).

Preferably, the reaction solvent of addition is tetrahydrofuran, carbondichloride, etc. The reaction temperature is preferably from −10° C. to−50° C., more preferably is −20° C.

Another aspect of the present invention is to provide a use forantitumor drug of said gambogenic acid derivative. The gambogenic acidanticancer drugs can be an injection, powder and other formulations.

The tumors include, but are not limited to, human skin cancer, humanthyroid cancer, human breast cancer, human gastric cancer, humancolorectal cancer, human liver cancer, human lung cancer, human ovariancancer, human head and neck cancer, human kidney cancer, human bladdercancer, human sarcoma (bone, cartilage, striated muscle, etc.), humanmalignant lymphoma, human leukemia, human prostate cancer, humanmalignant glioma, human cervical cancer, human esophageal cancer, humantesticular cancer, human malignant teratoma.

The gambogenic acid derivative of the present invention has betterantitumor activity, better security and simplified preparation byexperimental verification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart of a first method for gambogenic acid derivativein accordance with the present invention;

FIG. 2 is a flow chart of a second method for gambogenic acid derivativein accordance with the present invention;

FIG. 3 is a flow chart of a third embodiment for gambogenic acidderivative in accordance with the present invention;

FIG. 4 is a flow chart of a fourth embodiment for gambogenic acidderivative in accordance with the present invention;

FIG. 5 is a flow chart of a fifth embodiment for gambogenic acidderivative in accordance with the present invention.

DETAIL DESCRIPTION OF THE INVENTION

The present invention provides a gambogenic acid derivative, a salt ofgambogenic acid derivative, and the preparation method and use of saidgambogenic acid derivative.

The structure of the gambogenic acid derivative of the present inventionis as shown in Formula (I) and/or (II), and is preferably any one ofFormula (III) to (VI). The first embodiment of gambogenic acidderivative preparation of the present invention as shown in FIG. 1, theraw materials is gambogenic acid, R₂ and R₃ introduced, wherein theorder of the introduction of R₂ and R₃ can be adjusted.

The second embodiment of gambogenic acid derivative preparation of thepresent invention as shown in FIG. 2, the raw materials are gambogenicacid or the gambogenic acid derivative prepared from the firstembodiment, and carbonyl group of C₆ carbon is reduced to a hydroxylgroup.

The third embodiment for gambogenic acid derivatives preparation of thepresent invention as shown in FIG. 3, the raw materials is gambogenicacid or the gambogenic acid derivative prepared from the firstembodiment or the second embodiment, and then the gambogenic acidderivative obtained by esterification with R⁴OH, or by acidificationwith R⁵R⁶NH or

The fourth embodiment for gambogenic acid derivatives preparation of thepresent invention as shown in FIG. 4, the raw material is gambogenicacid, or the gambogenic acid derivative as shown in Formula (VII), orthe gambogenic acid derivative as shown in Formula (VIII), and thedouble bond between C₈ and C₉ was oxidized to prepare gambogenic acidderivative.

The fifth embodiment for gambogenic acid derivatives preparation of thepresent invention as shown in FIG. 5, the raw material is gambogenicacid, or the gambogenic acid derivative as shown in Formula (VII), orthe gambogenic acid derivative as shown in Formula (VIII), and thegambogenic acid derivative obtained by addition on double bond betweenthe C₉ and C₁₀ by the organic copper reagent RCu.

As shown in FIG. 1 to FIG. 5 and Formula (I) to (VIII):

A is —CO— or —HC(OH)—; R¹ is selected from:

1) —OR⁴;

wherein R⁴ is selected from the group consisting of any one of thefollowing: hydrogen, straight chain or branched chain C₁ to C₁₀ alkylgroup, or alkyl group containing optionally 1 to 3 substituted groupincluding oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group,C₁ to C₁₀ alkoxycarbonyl group, aryloxy group; C₃-C₈ cycloalkyl group,C₁ to C₁₀ alkyl group substituted by 1, 2 or 3 heteroatoms; alkylarylgroup includes C₁ to C₁₀ alkyl group substituted by aromatic group andC₁ to C₁₀ alkyl group optionally substituted by 1 to 3 substitutedaromatic group including acyl group, —OCH₂O—, halogen, haloalkyl group,aryl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxylgroup, acyloxy group, C₁ to C₁₀ alkoxy group; heteroarylalkyl groupincludes C₁ to C₁₀ alkoxy group substituted by heteroaryl group, and C₁to C₁₀ alkyl group optionally substituted by any heteroaryl groupincluding heteroaryl group, C₁ to C₁₀ alkyl group, aralkyl group, C₃ toC₈ cycloalkyl group, C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group,aromatic group and C₁ to C₆ amide group; straight chain or branchedchain C₂ to C₁₀ alkenyl group or alkynyl group including optionally 1 to3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group and C₁ to C₁₀heteroalkyl group including 1, 2 or 3 heteroatoms; C₄ to C₁₀cycloalkenyl, C₄ to C₁₀ alkynyl group, or alkynyl group includingoptionally 1 to 3 substituted groups including oxygen group, halogen,aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxygroup, amide group, C₁ to C₆ acyl group, C₁ to C₁₀ alkoxy group, aryloxygroup and C₁ to C₁₀ heteroalkyl group including optionally 1, 2 or 3heteroatoms.

2) —NR⁵R⁶;

wherein R⁵ and R⁶ may be identical or different, and are independentlyselected from any one of the substituted groups as follows: hydrogen;straight chain or branched C₁ to C₁₀ alkyl group or C₁ to C₁₀ alkylgroup containing optionally 1 to 3 substituted group including oxygengroup, halogen, C₁ to C₁₀ alkoxy group, acyloxy group, C₁ to C₁₀alkoxyacyl group, aryloxy group; C₃ to C₈ cycloalkyl group; C₁ to C₁₀alkyl group substituted by 1, 2 or 3 heteroatoms; alkylaryl groupincluding C₁ to C₁₀ alkyl group substituted by aromatic group and C₁ toC₁₀ alkyl group substituted by optionally 1 to 3 substituted aromaticgroups including acyl group, —OCH₂O—, halogen, haloalkyl group, hydroxylgroup, aryl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkyl group,acyloxy group, C₁ to C₁₀ alkoxy group; heteroarylalkyl group includingC₁ to C₁₀ alkoxy group substituted by heteroaryl group, and C₁ to C₁₀alkyl group optionally substituted by any heteroaryl group includingheteroaryl group, C₁ to C₁₀ alkyl group, aralkyl group, C₃ to C₈cycloalkyl group, C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group,aromatic group and C₁ to C₆ amide group; straight chain or branchedchain C₂ to C₁₀ alkenyl group or alkenyl group containing optionally 1to 3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy groupand C₁ to C₁₀ heteroalkyl group containing 1, 2 or 3 heteroatoms; C₄ toC₁₀ cycloalkenyl, C₄ to C₁₀ alkynyl group, or alkynyl group containingoptionally 1 to 3 substituted groups including oxygen group, halogen,aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxygroup, amide group, C₁ to C₆ acyl group, C₁ to C₁₀ alkoxy group, aryloxygroup and C₁ to C₁₀ heteroalkyl group including 1, 2 or 3 heteroatoms.

wherein s and t are positive integers, and the sum of s and t is anatural number of 2 to 10;

m is 0, 1, 2 or 3, represents the number of the substituted group on R⁷of the ring;

n is 0, 1, 2 or 3, represents the number of B on the ring; B is carbon,nitrogen or oxygen;

the groups of R⁷, R⁸ are identical with the group of R⁵, or carbonylgroup, imino group, oxime group, aliphatic group; or when B is tertiarynitrogen, R⁸ is oxygen, and so as to form nitrogen oxides with B;

R² is selected from any one of the substituted groups as follows:hydrogen, straight chain or branched chain C₁ to C₁₀ alkyl group, C₃ toC₈ cycloalkyl group, aromatic group or aromatic group substituted by C₁to C₁₀ alkyl, heteroaryl group, acyl group substituted by C₁ to C₁₀alkyl or acyl group substituted by aromatic group;

R³ is selected from any one of the substituted groups as follows:hydrogen, C₁ to C₁₀ acyl group substituted by alkyl group or aryl groupsubstituted by aromatic group;

R is selected from any one of the substituted groups as follows:hydrogen, straight chain or branched chain C₁ to C₁₀ alkyl group, C₃ toC₈ cycloalkyl group, straight chain or branched chain C₂ to C₁₀ alkenylgroup or C₃ to C₈ cycloalkenyl group, phenyl group or phenyl groupsubstituted by C₁ to C₁₀ alkyl group, C₂ to C₆ alkynyl group,nucleophiles containing secondary amine group including straight chainor branched chain alkyl amino group, straight chain or branched chainalkenyl amino group; aromatic or aromatic alkylamino group, the amineobtained by addition of chain alkynyl amine group and α,β-unsaturatedketones.

However, R, R¹, R², R³ are not simultaneously hydrogen on the Formula(I).

Other objectives, advantages and novel features of the invention willbecome more apparent from the following detailed description when takenin conjunction with the accompanying drawings.

Example 1 Preparation of methyl gambogenic acid

R¹ is a methyl group in Formula (VI).

With reference to FIG. 3, 20 mg gambogenic acid, 6.5 mg sodiumhydrogencarbonate, 1 ml DMA (N, N-dimethylacetamide), 15 μl iodomethanewere added into a 10 ml reaction flask and in the dark at roomtemperature.

Progress of the reaction was monitored by thin layer chromatography(TLC). After completion of the reaction, the reaction solution waspoured into 50 ml water, extracted with ether, washed with saline, driedby anhydrous sodium sulfate, and chromatographed (eluent is ethylacetate/petroleum ether, the volume ratio is 1:12) to obtain 9 mgorange-yellow jelly.

Example 2 Preparation of 6-methoxy methyl ester gambogenic acid

R¹ is methyl group, R² is methyl group, and R³ is H in the Formula(III).

With reference to FIG. 1, 20 mg methyl gambogenic acid obtained from theexample 1, 12 mg potassium, 1 ml DMA, 15 μl iodomethane were added intoa 25 ml reaction flask and in the dark at room temperature.

After completion of the reaction, the reaction solution was poured into50 ml water, and extracted with ether, washed with water, dried andchromatographed (eluent is ethyl acetate/petroleum ether, the volumeratio is 1:12) to obtain 12 mg orange-yellow jelly.

Example 3 Preparation of ethyl ester gambogenic acid

R¹ is an ethyl group in Formula (VI).

With reference to FIG. 3, 20 mg gambogenic acid, 6.5 mg sodiumbicarbonate, 1 ml DMA, and 15 μl bromoethane were added into a 10 mlreaction flask and in the dark at room temperature.

After completion of the reaction, the reaction solution was poured into50 ml water conductivity, extracted with ether, chromatographed (eluentis ethyl acetate/petroleum ether, the volume ratio is 1:12) to obtain 9mg orange-yellow jelly.

Example 4 Preparation of 6-ethoxyl gambogenic acid ethyl ester

R¹ is ethyl group, R² is ethyl group, R³ is H in Formula (III).

With reference to FIG. 1, 20 mg methyl gambogenic acid obtained from theexample 1, 6 mg potassium carbonate, 1 ml DMA (N,N-dimethylacetamide),15 μl bromoethane were added into a 25 ml reaction flask and in the darkat room temperature.

After completion of the reaction, the reaction solution was poured into50 ml water, extracted with ether, washed with water, dried andchromatographed (eluent is ethyl acetate/petroleum ether) (the volumeratio is 1:12) to obtain 9 mg orange-yellow jelly.

Example 5 Preparation of piperidine gambogenic acid

R¹ is

in Formula (VI).

With reference to FIG. 3, 15.6 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 6 mg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide carbodiimide hydrochloride(EDCI), 3.6 mg 1-hydroxybenzotriazole triazole (HOBT), 4.8 μl anhydrouspiperidine and 0.4 ml dichloromethane were dubbed into the ice-solution.

The ice-solution was warmed naturally to room temperature and stirred toobtain a reaction solution. After completion of the reaction, thereaction solution was diluted with 50 ml dichloromethane, washed with0.5 M aqueous sulfuric acid solution, saturated saline, dried overanhydrous sodium sulfate and then the solvent was evaporated,chromatographed (eluent is ethyl acetate/petroleum ether/diethylchloromethane) (the volume ratio is 1:4:1), and then eluted to obtain 5mg yellow jelly.

Example 6 Preparation of diethylamide gambogenic acyl

R¹ is —N(CH₃2 CH₃)₂.

With reference to FIG. 3, 20 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 6 mg EDCI, 3.6 mg HOBT, 10 μl ethylenediamineand 0.5 ml dichloromethane were dubbed into the ice-solution.

The ice-solution was warmed naturally to room temperature and stirred toobtain a reaction solution. After completion of the reaction, thereaction solution was diluted with 50 ml dichloromethane, washed with0.5 M aqueous sulfuric acid solution, saturated saline, dried withanhydrous sodium sulfate and then the solvent was evaporated,chromatographed (eluent is ethyl acetate/petroleum ether/diethylchloromethane) (the volume ratio is 1:4:1), and then eluted to obtain 7mg yellow jelly.

Example 7 Preparation of morpholine gambogenic acid

R¹ is

With reference to FIG. 3, 15.6 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 10 mg EDCI, 6 mg HOBT, 5 μl morpholine and 0.4ml dichloromethane were dubbed into the ice-solution.

The ice-solution was warmed naturally to room temperature and stirred toobtain a reaction solution. 3 mg HOBT, 5 μl morpholine were added to thereaction solution additionally. After completion of the reaction, thereaction solution was diluted with 50 ml dichloromethane, and thenwashed with 0.5 M sulfuric acid aqueous solution, saturated saline,dried with anhydrous sodium sulfate, and then the solvent wasevaporated, chromatographed (eluent is chloroform/ethyl acetate) (thevolume ratio is 8:1), and then eluted to obtain 5 mg orange-yellowjelly.

Example 8 Preparation of 12-hydroxy gambogenic acid

The Formula of 12-hydroxy gambogenic acid is as follows:

With reference to FIG. 2, 20 mg gambogenic acid and 4 ml methanol wereice-bath cooled to −5° C. to form an ice-solution in a 10 ml reactionflask. The ice-solution was added 44 mg sodium borohydride to form amixture. The mixture was dried for 1 h, and then warmed naturally toroom temperature for 3 hours to complete reaction.

3 M hydrochloric acid aqueous solution was added to quench the reactionto form a reaction solution. The reaction solution was diluted with 50ml ethyl acetate, and then washed with 0.5 M hydrochloric acid aqueoussolution, saturated saline, and then dried with anhydrous sodiumsulfate, and then the solvent was evaporated, chromatographed (eluent isethyl acetate acetate/dichloromethane) (the volume ratio is 1:4), andthen eluted to obtain 9 mg orange-yellow jelly.

Example 9 Preparation of 8,9-epoxy gambogenic acid

The Formula of 8,9-epoxy gambogenic acid structure is as follows:

With reference to FIG. 4, 50 mg gambogenic acid, 0.5 ml and 2M sodiumhydroxide aqueous solution, and 0.2 ml hydrogen peroxide were added intoa 10 ml reaction flask and reacted at room temperature to form areaction solution.

After completion of the reaction, the reaction solution was extracted byethyl acetate, and washed with 1.0 M hydrochloric acid aqueous solution,saturated saline, and dried with anhydrous sodium sulfate, and then thesolvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether) (the volume ration is 1:3), and then eluted toobtain 12 mg orange-yellow jelly.

Example 10 Preparation of gambogenic acyl n-butylamine

A is —CO—, R¹ is —NH—(CH₂)₁₀—CH₃, in the Formula (VI).

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 6 μl n-butylamine and 0.5 ml dichloromethane were added intothe ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed by silicagel column(eluent is ethyl acetate/petroleum ether/dichloromethane) (the volumeratio is 1:8:1), and then eluted to obtain 7 mg orange-yellow jelly.

Example 11 Preparation of gambogenic acyl undecylamine

A is —CO—, R¹ is —NH—(CH₂)₁₀—CH₃, in Formula (VI).

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 6 μl n-undecylamine and 0.5 ml dichloromethane were added intothe ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed by silicagel column(eluent is ethyl acetate/petroleum ether/dichloromethane (the volumeratio is 1:8:1), and then eluted to obtain 7 mg orange-yellow jelly.

Example 12 Preparation of gambogenic acyl isopropylamine

A is —CO—, R¹ is —NH—CH(CH₃)₂, in Formula (VI).

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 5 μl isopropylamine and 0.5 ml dichloromethane were added intothe ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed by silicagel column(eluent is ethyl acetate/petroleum ether/dichloromethane) (the volumeratio is 1:8:1), and then eluted to obtain 7 mg orange-yellow jelly.

Example 13 Preparation of gambogenic acyl dipropylamine

A is —CO—, R¹ is —NHR⁵R⁶, wherein R⁵ and R⁶ are both propyl group in theFormula (VI).

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 8 μl dipropylamine and 0.5 ml dichloromethane were added intothe ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed by silicagel column(eluent is ethyl acetate/petroleum ether/dichloromethane (the volumeratio is 1:4:1), and then eluted to obtain 7 mg orange-yellow jelly.

Example 14 Preparation of gambogenic acyl isobutylamine

A is —CO—, R¹ is —NH—C(CH₃)—CH₂—CH₃ in Formula (VI).

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 6 μl isobutylamine and 0.5 ml dichloromethane were added intothe ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed by silicagel column(eluent is ethyl acetate/petroleum ether/dichloromethane (the volumeratio is 1:8:1), and then eluted to obtain 7 mg orange-yellow jelly.

Example 15 Preparation of gambogenic acyl(2,6-dimethylpiperidine)

R¹ is

With reference to FIG. 3, 20 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 10 mg EDCI, 4.5 mg HOBT, 8 μl2,6-dimethylpiperidine and 0.5 ml dichloromethane were added into theice-solution. The ice-solution was warmed naturally to room temperatureand stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated by saline three times, dried with anhydrous sodiumsulfate, and then the solvent was evaporated, chromatographed (eluent isethyl acetate/benzene) (the volume ratio is 1:8), and then eluted toobtain 5 mg orange-yellow jelly.

Example 16 Preparation of gambogenic acyl pyrrolidine

R¹ is

With reference to FIG. 3, 20 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 10 mg EDCI, 4.5 mg HOBT, 5 μl pyrrolidine and0.5 ml dichloromethane were added into the ice-solution. Theice-solution was warmed naturally to room temperature and stirred toobtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated by saline three times, dried with anhydrous sodiumsulfate, and then the solvent was evaporated, chromatographed (eluent isethyl acetate/petroleum ether) (the volume ratio is 1:4), and theneluted to obtain 6 mg orange-yellow jelly.

Example 17 Preparation of gambogenic acid cyclohexylamine

R¹ is

pyrrolidine FIG. 3, 20 mg gambogenic acid and 0.5 ml dichloromethanewere ice-bath cooled to 0° C. to form an ice-solution in a 10 mlreaction flask. 10 mg EDCI, 4.5 mg HOBT, 7 μl cyclohexylamine and 0.5 mldichloromethane were added into the ice-solution. The ice-solution waswarmed naturally to room temperature and stirred to obtain a reactionsolution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 18 Preparation of gambogenic acyl(ethoxyethylamine)

R¹ is —NH—(CH)₂—O—CH₂—CH₃.

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 5 mg ethoxyethylamine and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 5 mg orange-yellow jelly.

Example 19 Preparation of gambogenic acid benzylamine

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 7 μl benzylamine and 0.5 ml dichloromethane were added into theice-solution. The ice-solution was warmed naturally to room temperatureand stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 20 Preparation of gambogenic acyl ethoxycarbonyl methylamine

R¹ is —NH—CH₂—CO—O—CH₂—CH₃.

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 10 mg glycine ethyl ester and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 21 Preparation of gambogenic acyl piperazine

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 4 mg piperazine and 0.5 ml dichloromethane were added into theice-solution. The ice-solution was warmed naturally to room temperatureand stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/methanol) (the volume ratio is 10:1), and then eluted to obtain7 mg orange-yellow jelly.

Example 22 Preparation of gambogenic acyl methylpiperazine and citricacid salt Thereof

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 7 μl methylpiperazine and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Gambogenic acyl methylpiperazine was dissolved in ethanol, ethanol thesolution having citric acid was added dropwise, the resultingprecipitate was dissolved by heating, cooling pale yellow precipitate,filtered, dried to obtain gambogenic acyl methylpiperazine and citricacid salt thereof.

Example 23 Preparation of gambogenic acyl benzylpiperazine and citricacid salt Thereof

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 11 μl benzylpiperazine and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 24 Preparation of gambogenic acyl(4-acetylpiperazinyl)

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 5 mg acetylpiperazinyl and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 25 Preparation of gambogenic acyl cyclopropanamine

R¹ is

20 mg gambogenic acid and 0.5 ml dichloromethane were ice-bath cooled to0° C. to form an ice-solution in a 10 ml reaction flask. 10 mg EDCI, 4.5mg HOBT, 5 μl cyclopropanamine and 0.5 ml dichloromethane were addedinto the ice-solution. The ice-solution was warmed naturally to roomtemperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/) (the volume ratio is 1:8), and then eluted toobtain 5 mg orange-yellow jelly.

Example 26 Preparation of gambogenic acid (3-methoxy-pyrrolidine)

R¹ is

Referring to FIG. 3, 20 mg gambogenic acid and 0.5 ml dichloromethanewere ice-bath cooled to 0° C. to form an ice-solution in a 10 mlreaction flask. 10 mg EDCI, 4.5 mg HOBT, 6 mg 3-methoxy-pyrrolidine and0.5 ml dichloromethane were added into the ice-solution. Theice-solution was warmed naturally to room temperature and stirred toobtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 4 mg orange-yellow jelly.

Example 27 Preparation of gambogenic acid [3-(3-methoxy-pyrrolidineyl)-propyl]ester

R¹ is

With reference to FIG. 3, 20 mg gambogenic acid and 0.5 mldichloromethane were ice-bath cooled to 0° C. to form an ice-solution ina 10 ml reaction flask. 10 mg EDCI, 4.5 mg HOBT, 10 mg3-(3-methoxy-pyrrolidine yl)-propanol and 0.5 ml dichloromethane wereadded into the ice-solution. The ice-solution was warmed naturally toroom temperature and stirred to obtain a reaction solution.

After completion of the reaction, the reaction solution was diluted with50 ml dichloromethane, and then washed with 0.5 M sulfuric acid aqueoussolution, saturated saline, dried with anhydrous sodium sulfate, andthen the solvent was evaporated, chromatographed (eluent is ethylacetate/petroleum ether/dichloromethane) (the volume ratio is 1:4:1),and then eluted to obtain 7 mg orange-yellow jelly.

Example 28 Preparation of 10-methyl gambogenic acid

R² and R³ is H, R is methyl group in Formula (V).

With reference to FIG. 5, 24 mg magnesium, 1 ml ether and 0.07 mliodomethane were dropwised into a 5 ml reaction flask, and maintainingmicro-boiling to obtain a clear Grignard reagent. 100 mg cuprous iodidewas dissolved in tetrahydrofuran to form a suspension, and then thesuspension was cooled to −40° C. and added 0.1 ml prepared Grignardreagent to form gray suspension.

20 mg gambogenic acid was added into tetrahydrofuran at −20° C.

After completion of the reaction, 1 M hydrochloric acid quenched thereaction, ether extraction, and chromatographed separation to obtain 7mg orange-yellow jelly.

The compounds synthesized from the present invention were studied bysulforhodamine B protein staining (sulfothodalnine B, SRB) andmiceroculture tetrazolinetetrozohuln (MTT) colorimetric methodrespectively for in vitro anti-tumor activity (Cancer Res., 1988, 48(3): 589).

The concentration gradient of the test compounds of the presentinvention is 10⁻⁴M, 10⁻⁵M, 10⁻⁶M, 10⁻⁷M, 10⁻⁸M, and the test compoundsare 6-methoxy methyl ester gambogenic acid, ethyl ester gambogenic acid,6-ethoxy ethyl ester gambogenic acid, 6-acyl gambogenic acid, piperidinegambogenic acid, diethylamide gambogenic acyl, morpholine gambogenicacid, and 12-hydroxy gambogenic acid, and 8,9-epoxy gambogenic acid. Thetest compounds and positive control gambogenic acid were diluted withdimethyl sulfoxide.Inhibition rate(%)=[(control group OD value−administered group ODvalue)/control group OD value]×100%

Assessment of results:

Invalid: 10⁻⁵M inhibition rate<85%;

Weak: 10⁻⁵M inhibition rate≧85% or 10⁻⁶M>50%;

Potent: 10⁻⁶M inhibition rate≧75% or 10⁻⁷M inhibition rate>50%.

1. The Growth Inhibition of Tumor Cell Cal27

Human oral squamous cells carcinoma Cal27 were cultured in DMEMcontaining 10% fetal bovine serum (FBS), the cells with long-growthphase were forming suspension and culturing in 96-well plates. 10 μltest compounds of different concentrations as experimental group wereadded into each well of the 96-well plates. Blank control group receivedan equal volume containing the highest concentration of solvent (ie,10⁻⁴M dimethyl sulfoxide) in DMEM. After incubation at 37° C. under 5%carbon dioxide conditions for 72 hours, the cells were fixed withtrichloroacetic acid, and each well was added with 100 μl SRB solution,unbound SRB was washed away, and then OD values were measured at 550 nmby an automatic plate reader spectrophotometer. A tumor cell groupwithout drugs is a blank control group. The growth inhibition rate oftumor cells was calculated and the results were as shown in Table 1.

TABLE 1 the growth inhibition of Cal27 tumor cell to the test compoundsconcentration 10⁻⁴M 10⁻⁵M 10⁻⁶M 10⁻⁷M 10⁻⁸M efficacy gambogenic acid 100100 5 0 0 invalid 6-methoxy methyl ester 100 100 100 0 0 potentgambogenic acid ethyl ester gambogenic 100 100 98 0 0 potent acid6-ethoxy ethyl ester 100 100 94 0 0 potent gambogenic acid 6-acylgambogenic acid 100 100 96 0 0 potent piperidine gambogenic 100 100 70 00 invalid acid diethylamide gambogenic 100 100 100 23 0 potent acylmorpholine gambogenic 100 100 100 14 0 potent acid 12-hydroxy gambogenic100 100 100 0 0 potent acid 8,9-epoxy gambogenic 100 100 100 0 0 potentacid

TABLE 2 the growth inhibition rate of tumor cells MCF-7 to the testcompounds concentration 10⁻⁴M 10⁻⁵M 10⁻⁶M 10⁻⁷M 10⁻⁸M efficacygambogenic acid 100 100 0 0 0 invalid 6-methoxy methyl ester 100 100 800 0 potent gambogenic acid ethyl ester gambogenic 100 100 96 0 0 potentacid 6-ethoxy ethyl ester 100 100 86 0 0 potent gambogenic acid 6-acylgambogenic acid 100 100 83 0 0 potent piperidine gambogenic 100 100 67 00 invalid acid diethylamide gambogenic 100 100 84 0 0 potent acylmorpholine gambogenic 100 100 78 14 0 potent acid 12-hydroxy gambogenic100 100 82 0 0 potent acid 8,9-epoxy gambogenic 100 100 80 0 0 potentacid2. The Growth Inhibition of Tumor Cell MCF-7

Human breast cancer cells MCF-7 were cultured in DMEM containing 10%FBS, the cell with long-growth phase was formed into suspension andcultured in 96-well plates. The test compounds as experimental groupwith different concentrations were added into each well of the 96-wellplates. Blank control group received an equal volume containing thehighest concentration of solvent (ie, 10⁻⁴M dimethyl sulfoxide) in DMEM.After incubation at 37° C. under 5% carbon dioxide conditions for 72hours, each well was added with MTT to 1 mg/ml final concentration forincubation for 4 hours. The supernatant solution in each well wasaspirated and added with 200 μl DMSO to dissolve crystals, and then ODvalues were measured at 490 nm by an automatic plate readerspectrophotometer. A tumor cell group without drugs is a blank controlgroup. The growth inhibition rates of tumor cells were calculated andthe results were as shown in Table 2.

Accordingly, Tables 1 and 2 of the present invention indicate thatgambogenic acid derivatives have a stronger growth inhibition of tumorcell.

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent, orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features. From the above description, one skilled in the art caneasily ascertain the essential characteristics of the present invention,and without departing from the spirit and scope thereof, can makevarious changes and modifications of the invention to adapt it tovarious usages and conditions. Thus, other embodiments are also withinthe scope of the claims.

The invention claimed is:
 1. A gambogenic acid derivative of Formula (I)or Formula (II) as follows:

wherein: A is —CO— or —HC(OH)—; R² is selected from any one of thegroups as follows: hydrogen, straight chain or branched chain C₁ to C₁₀alkyl group, C₃ to C₈ cycloalkyl group, aromatic group or aromatic groupsubstituted by C₁ to C₁₀ alkyl, heteroaryl group, and acyl groupsubstituted by C₁ to C₁₀ alkyl or acyl group substituted by aromaticgroup; R³ is selected from any one of the groups as follows: hydrogen,acyl group substituted by C₁ to C₁₀ alkyl or aryl group substituted byaromatic group; R is selected from any one of the groups as follows:hydrogen, straight chain or branched chain C₁ to C₁₀ alkyl group, C₃ toC₈ cycloalkyl group, straight chain or branched chain C₂ to C₁₀ alkenylgroup or C₃ to C₈ cycloalkenyl group, phenyl group or phenyl groupsubstituted by C₁ to C₁₀ alkyl group, C₂ to C₆ alkynyl group,nucleophiles containing secondary amine group including straight chainor branched chain alkyl amino group, straight chain or branched chainalkenyl amino group; aromatic or aromatic alkylamino group, the amineobtained by addition of chain alkynyl amine group and α, β-unsaturatedketones; R¹ is selected from:

wherein R⁴ is selected from the group consisting of any one of thefollowing: hydrogen, straight chain or branched chain C₁ to C₁₀ alkylgroup, or alkyl group containing optionally 1 to 3 substituted groupsincluding oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group,C₁ to C₁₀ alkoxycarbonyl group, aryloxy group; C₃-C₈ cycloalkyl group,C₁ to C₁₀ alkyl group substituted by 1, 2 or 3 heteroatoms; alkylarylgroup including C₁ to C₁₀ alkyl group substituted by aromatic group andC₁ to C₁₀ alkyl group optionally substituted by 1 to 3 substitutedaromatic groups including acyl group, —OCH₂O—, halogen, haloalkyl group,aryl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxylgroup, acyloxy group, C₁ to C₁₀ alkoxy group; heteroarylalkyl groupincluding C₁ to C₁₀ alkoxy group substituted by heteroaryl group, and C₁to C₁₀ alkyl group optionally substituted by any heteroaryl groupincluding heteroaryl group, C₁ to C₁₀ alkyl group, aralkyl group, C₃ toC₈ cycloalkyl group, C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group,aromatic group and C₁ to C₆ amide group; straight chain or branchedchain C₂ to C₁₀ alkenyl group or alkenyl group including optionally 1 to3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group and C₁ to C₁₀heteroalkyl group including 1, 2 or 3 heteroatoms; C₄ toC₁₀cycloalkenyl, C₄ to C₁₀ alkynyl group, or alkynyl group includingoptionally 1 to 3 substituted group including oxygen group, halogen,aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxygroup, amide group, C₁ to C₆ acyl group, C₁ to C₁₀ alkoxy group, aryloxygroup and C₁ to C₁₀ heteroalkyl group including optionally 1, 2 or 3heteroatoms; R⁵ and R⁶ are independently selected from any one of thegroups as follows: hydrogen; straight chain or branched C₁ to C₁₀ alkylgroup or C₁ to C₁₀ alkyl group containing optionally 1 to 3 substitutedgroups including oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxygroup, C₁ to C₁₀ alkoxyacyl group, aryloxy group; C₃ to C₈ cycloalkylgroup; C₁ to C₁₀ alkyl group substituted by 1, 2 or 3 heteroatoms;alkylaryl group including C₁ to C₁₀ alkyl group substituted by aromaticgroup and C₁ to C₁₀ alkyl group substituted by optionally 1 to 3substituted aromatic groups including acyl group, —OCH₂O —, halogen,haloalkyl group, hydroxyl group, aryl group, C₃ to C₈ cycloalkyl group,C₁ to C₁₀ alkyl group, acyloxy group, C₁ to C₁₀ alkoxy group;heteroarylalkyl group includes C₁ to C₁₀ alkoxy group substituted byheteroaryl group, and C₁ to C₁₀ alkyl group optionally substituted byany heteroaryl group including heteroaryl group, C₁ to C₁₀ alkyl group,aralkyl group, C₃ to C₈ cycloalkyl group, C₁ to C₁₀ alkoxycarbonylgroup, carbamoyl group, aromatic group and C₁ to C₆ amide group;straight chain or branched C₂ to C₁₀ alkenyl group or alkenyl groupcontaining optionally 1 to 3 substituted groups including oxygen group,halogen, aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group,acyloxy group, amide group, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxygroup, aryloxy group, and C₁ to C₁₀ heteroalkyl group containing 1, 2 or3 heteroatoms; C₄ to C₁₀ cycloalkenyl, C₄ to C₁₀ alkynyl group, oralkynyl group containing optionally 1 to 3 substituted groups includingoxygen group, halogen, aromatic ring group, aralkyl group, C₁ to C₁₀alkoxy group, acyloxy group, amide group, C₁ to C₆ acyl group, C₁ to C₁₀alkoxy group, aryloxy group and C₁ to C₁₀ heteroalkyl group including 1,2 or 3 heteroatoms; s and t are positive integers, and the sum of s andt is a natural number of 2 to 10; m is 0, 1, 2 or 3, and represents thenumber of the substituted group on R⁷ of the ring; n is 0, 1, 2 or 3,and represents the number of B on the ring; B is carbon, nitrogen oroxygen; B is carbon, the groups of R⁷, R⁸ are identical with the groupof R⁵, or carbonyl group, imino group, oxime group, aliphatic group; orwhen B is tertiary nitrogen, R⁸ is oxygen, and so as to form nitrogenoxides with B; and, R⁴, R³, R², R¹ are not simultaneously hydrogen onthe Formula (I).
 2. The gambogenic acid derivative as claimed in claim1, wherein said gambogenic acid derivative is represented by Formula(III), Formula (IV) or Formula (V) as follows:

wherein R², R³, R⁴ are not simultaneously hydrogen on Formula (III); R,R², R³ are not simultaneously hydrogen on Formula (V).
 3. The gambogenicacid derivative as claimed in claim 1, wherein R⁴ is selected from thegroup consisting of any one of the groups as follows: hydrogen, methylgroup, ethyl group, propyl group, isopropyl group, butyl group, isobutylgroup, tert-butyl group, hexyl group, octyl group, C₁ to C₁₀ alkyl groupoptionally substituted by 1 to 3 substituted groups including any ofoxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group, C₁ to C₁₀alkoxyacyl group, aromatic group; cyclohexyl group, cyclopentyl group;cyclopropyl group, —CH₂CH₂OCH₂CH₃, —CH₂CH₂OCH₂CH₂OCH₂CH₃, —CH₂CH₂NHCH₃,—OCH₂O —, halogen, haloalkyl group, hydroxyl group, —CH₂CH₂N(CH₂CH₃)₂,—CH₂CH₂OCH₂CH₂NCH₃, benzyl group, phenethyl group, phenylpropyl group,tetrahydro-pyrrolyl group, piperidinyl group, morpholinyl group,—CH₂CH₂OCH₂CH₂OCH₂NHCH₃, —CH₂CH₂NHCH₂CH₃, —CH₂(N-ethyl-pyrrolidine),—CH₂C(CH₃)CH₂N(CH₃), C₁ to C₁₀ alkyl group substituted by optionally 1to 3 substituted aromatic groups including acyl group, aryl group, C₃ toC₈ cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxyl group, acyloxygroup, C₁ to C₁₀ alkoxy group; heteroarylalkyl group including C₁ to C₁₀alkoxy group substituted by heteroaryl group, and C₁ to C₁₀ alkyl groupoptionally substituted by any heteroaryl group including heteroarylgroup, C₁ to C₁₀ alkyl group, aralkyl group, C₃ to C₈ cycloalkyl group,C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group, aromatic group and C₁to C₆ amide group; straight chain or branched chain C₂ to C₁₀ alkenylgroup or alkenyl group containing optionally 1 to 3 substituted groupsincluding oxygen group, halogen, aromatic ring group, aralkyl group, C₁to C₁₀ alkoxy group, acyloxy group, amide group, C₁ to C₆ amine acylgroup, C₁ to C₁₀ alkoxy group, aryloxy group, and C₁ to C₁₀ heteroalkylgroup containing 1, 2 or 3 heteroatoms; C₄ to C₁₀ cycloalkenyl, C₄ toC₁₀ alkynyl group, or C₄ to C₁₀ alkynyl group containing optionally 1 to3 substituted groups including oxygen group, halogen, aromatic ringgroup, aralkyl group, C₁ to C₁₀ alkoxy group, acyloxy group, amidegroup, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy groupand C₁ to C₁₀ heteroalkyl group containing 1, 2 or 3 heteroatoms.
 4. Thegambogenic acid derivative as claimed in claim 1, wherein R⁵ and R⁶ areindependently selected from any one of the groups as follows: hydrogen,methyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl butyl group, tert-butyl group, hexyl group, octyl group; C₁ toC₁₀ alkyl group containing optionally 1 to 3 substituted groupsincluding hydroxyl group, amino group, C₁ to C₁₀ alkylamino group,oxygen group, halogen, C₁ to C₁₀ alkoxy group, acyloxy group, C₁ to C₁₀alkoxyacyl group, aryloxy group; cyclohexyl group, cyclopentyl group,cyclopropyl group, —CH₂CH₂OCH₂CH₃, —CH₂CH₂OCH₂CH₂OCH₂CH₃, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂OCH₂CH₂NCH₃, —CH₂(N-ethyl-pyrrolidine),tetrahydro-pyrrolyl group, piperidinyl group, morpholinyl group, benzylgroup, —CH₂CH₂OCH₂CH₂OCH₂NHCH₃, —CH₂CH₂NHCH₂CH₃, phenethyl group,phenylpropyl group, —CH₂C(CH₃)CH₂N(CH₃); C₁ to C₁₀ alkyl groupoptionally substituted by 1 to 3 substituted aromatic groups includingacyl group, —OCH₂O—, halogen, haloalkyl group, aryl group, C₃ to C₈cycloalkyl group, C₁ to C₁₀ alkyl group, hydroxyl group, acyloxy group,C₁ to C₁₀ alkoxy group; heteroarylalkyl group including C₁ to C₁₀ alkoxygroup substituted by heteroaryl group, and C₁ to C₁₀ alkyl groupoptionally substituted by any heteroaryl group including heteroarylgroup, C₁ to C₁₀ alkyl group, aralkyl group, C₃ to C₈ cycloalkyl group,C₁ to C₁₀ alkoxycarbonyl group, carbamoyl group, aromatic group and C₁to C₆ amide acyl group, straight chain or branched chain C₁ to C₁₀alkenyl group or alkynyl group containing optionally 1 to 3 substitutedgroups including oxygen group, halogen, aromatic ring group, aralkylgroup, C₁ to C₁₀ alkoxy group, acyloxy group, amide group, C₁ to C₆amine acyl group, C₁ to C₁₀ alkoxy group, aryloxy group and C₁ to C₁₀heteroalkyl group containing 1, 2 or 3 heteroatoms; C₄ to C₁₀cycloalkenyl, C₄ to C₁₀ alkynyl group, or C₄ to C₁₀ alkynyl groupcontaining optionally 1 to 3 substituted groups including oxygen group,halogen, aromatic ring group, aralkyl group, C₁ to C₁₀ alkoxy group,acyloxy group, amide group, C₁ to C₆ amine acyl group, C₁ to C₁₀ alkoxygroup, acyloxy group, and C₁ to C₁₀ heteroalkyl group containing 1, 2 or3 heteroatoms.
 5. The gambogenic acid derivative as claimed in claim 1,wherein R³ is selected from any one of the groups as follows: hydrogen,formyl group, acetyl group, carbamoyl group, phenyl group, benzyl group,and phenylacetyl group.
 6. The gambogenic acid derivative as claimed inclaim 1, wherein R² is selected from any one of groups as follows:hydrogen, methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, tert-butyl group, hexyl group, octyl group,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, cycloheptyl group, benzyl group, phenethyl group, furyl group,pyranyl group, 2H-pyrrolyl group, pyrrolyl group, imidazolyl group,pyrazolyl group, pyridyl group, formyl group, acetyl group, carbamoylacyl group, phenyl group, benzyl group, and phenylacetyl group.
 7. Thegambogenic acid derivative as claimed in claim 1, wherein R is selectedfrom any one of groups as follows: methyl group, ethyl group, propylgroup, isopropyl group, butyl group, isobutyl group, tert-butyl group,hexyl group, octyl group, cyclohexyl group, cyclopentyl group, vinylgroup, butene group, hexenyl group, cyclohexenyl group, cyclopentenylgroup, phenyl group, benzyl group, phenethyl group, phenylpropyl group,butynyl group, hexynyl group, morpholinyl group, piperidinyl group, andpiperazinyl group.
 8. The gambogenic acid derivative as claimed in claim1, wherein R¹ is selected from:

wherein R⁷ is selected from any one of the following groups: substitutedgroup as defined in R⁵, carbonyl group; imino group, oxime group,aliphatic group; m, n is 0, 1, 2 or 3; B is carbon, nitrogen or oxygen;the group of R⁸ is identical with R⁵, or is oxygen so as to formnitrogen oxides with B.
 9. A salt of gambogenic acid derivatives asclaimed in claim 1, wherein the salt is with inorganic acid, organicacid, inorganic base or organic base.
 10. A method for preparing agambogenic acid derivative, the method comprising introducing R² and R³to the gambogenic acid or gambogenic acid derivative of Formula (VI)

to obtain the gambogenic acid derivative as shown in Formula (VII):


11. A method for preparing a gambogenic acid derivative, the methodcomprising reducing the carbonyl group of C₆ carbon to obtain agambogenic acid derivative as shown in Formula (VIII), and/or byesterification or acidification with R⁴OH, R⁵R⁶NH or

to obtain a gambogenic acid derivative as shown in Formula (III).


12. A method for preparing a gambogenic acid derivative, the methodcomprising using the gambogenic acid, the gambogenic acid derivative asshown in Formula (VII), or the gambogenic acid derivative as shown inFormula (VIII) as raw material; and oxidizing the double bond between C₉and C₁₀ by peroxidant in alkaline condition to obtain a gambogenic acidderivative as shown in Formula (II).
 13. A method for preparing agambogenic acid derivative, the method comprising preparing thegambogenic acid derivative as shown in Formula (I) by 1,4-addition ondouble bond between the C₉ and C₁₀ using organic copper reagent RCu withthe gambogenic acid, the gambogenic acid derivative as shown in Formula(VII), or gambogenic acid derivative as shown in Formula (VIIII).
 14. Ananticancer drug comprising an active ingredient of a gambogenic acidderivative as claimed in claim 1.